Liu Bin, Yang Yonghui, Chernishof Vasili, Loo Rachel R Ogorzalek, Jang Hyunduk, Tahk Samuel, Yang Randy, Mink Sheldon, Shultz David, Bellone Clifford J, Loo Joseph A, Shuai Ke
Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
Cell. 2007 Jun 1;129(5):903-14. doi: 10.1016/j.cell.2007.03.056.
How inflammatory stimuli signal to the nucleus to restrict inflammation is poorly understood. Protein inhibitor of activated STAT1 (PIAS1), a transcriptional regulator that possesses small ubiquitin-related modifier (SUMO) E3 ligase activity, inhibits immune responses by selectively blocking the binding of NF-kappaB and STAT1 to gene promoters. We report here that PIAS1 becomes rapidly phosphorylated on Ser90 residue in response to various inflammatory stimuli. Mutational studies indicate that Ser90 phosphorylation is required for PIAS1 to repress transcription. Upon TNF treatment, wild-type PIAS1, but not the Ser90A mutant, becomes rapidly associated with the promoters of NF-kappaB target genes. Furthermore, IKKalpha, but not IKKbeta, interacts with PIAS1 in vivo and mediates PIAS1 Ser90 phosphorylation, a process that requires the SUMO ligase activity of PIAS1. Our results identify a signaling pathway in which proinflammatory stimuli activate the IKKalpha-mediated sumoylation-dependent phosphorylation of PIAS1 for the immediate repression of inflammatory gene activation.
炎症刺激如何向细胞核发出信号以限制炎症，目前尚不清楚。活化STAT1蛋白抑制剂（PIAS1）是一种具有小泛素相关修饰物（SUMO）E3连接酶活性的转录调节因子，它通过选择性阻断NF-κB和STAT1与基因启动子的结合来抑制免疫反应。我们在此报告，PIAS1在受到各种炎症刺激后，其Ser90残基会迅速发生磷酸化。突变研究表明，Ser90磷酸化是PIAS1抑制转录所必需的。在TNF处理后，野生型PIAS1而非Ser90A突变体迅速与NF-κB靶基因的启动子结合。此外，IKKα而非IKKβ在体内与PIAS1相互作用并介导PIAS1的Ser90磷酸化，这一过程需要PIAS1的SUMO连接酶活性。我们的结果确定了一条信号通路，其中促炎刺激激活IKKα介导的PIAS1的SUMO化依赖性磷酸化，以立即抑制炎症基因的激活。
